Alcohol is one of the most popularly consumed and abused drugs in the world. The pleasurable and disinhibiting effects of alcohol consumption have been enjoyed by humankind for thousands of years. For some, however, alcohol consumption leads to alcohol addiction, a devastating illness with enormous medical and societal costs. In humans, long-term alcohol use leads to the development of tolerance, most simply defined as an acquired resistance to the inebriating effects of ethanol. Alcoholics can appear sober at blood alcohol levels that would be severely intoxicating or even fatal to naive individuals. The overall goal of this proposal is to decipher the relationship between the molecular mechanisms contributing to ethanol tolerance and those that mediate the addicting effects of the drug. Drosophila melanogaster, with its accessibility to genetic, behavioral and molecular analyses, has been developed as a powerful model system to study the mechanisms underlying ethanol intoxication and tolerance development. In this proposal, we plan to study a collection of existing mutants with defects in ethanol tolerance in a series of newly-developed assays that quantify ethanol consumption, preference, conditioned preference, and relapse in Drosophila. These studies will provide new insights into the relationship between the molecular mechanisms of ethanol tolerance and those underlying the rewarding and addicting properties of ethanol. In addition, these genes and their products will be attractive candidate targets for therapeutic intervention. PUBLIC HEALTH RELEVANCE: Low doses of ethanol in naive individuals lead to intoxication, with pleasurable effects such as euphoria and loss of social inhibitions, as well as aversive effects such as loss of motor coordination, dehydration, and sedation. However, chronic exposure to high ethanol doses is toxic, leading to severe and irreversible damage to the brain, liver, and kidneys. Alcohol abuse is facilitated by the development of tolerance, most simply defined as an acquired resistance to the effects of the drug. In humans, tolerance is thought to develop rapidly to the aversive effects of ethanol, and to a lesser extent to its pleasurable properties. This initial imbalance between aversive and enjoyable effects has been suggested to encourage greater intake, which over time leads to the development of physical dependence and possibly addiction. In this proposal we plan to study the relationship between ethanol tolerance and ethanol addiction, using the powerful molecular genetics offered by the model organism Drosophila melanogaster. These studies will provide new insights into the relationship between the genes involved in ethanol tolerance and those mediating the rewarding and addicting properties of ethanol. These genes and their products will be attractive candidate targets for therapeutic intervention.